Chloasma amelioration composition and dullness amelioration composition

ABSTRACT

The present invention provides a composition that can effectively improve melasma and a composition that can effectively reduce skin dullness. The composition for improving melasma comprises a purine nucleic acid-related substance and a pharmaceutically or cosmetically acceptable carrier, and exhibits an excellent melasma improving effect due to the action of the purine nucleic acid-related substance contained. The composition for reducing skin dullness comprises a purine nucleic acid-related substance and a pharmaceutically or cosmetically acceptable carrier, and exhibits an excellent effect of reducing skin dullness due to the action of the purine nucleic acid-related substance contained.

TECHNICAL FIELD

The present invention relates to a composition that can effectivelyimprove melasma. The present invention also relates to a method forimproving melasma. Further, the invention relates to a composition thatcan effectively reduce skin dullness. The invention also relates to amethod for reducing skin dullness.

BACKGROUND OF THE INVENTION

Melasma is a disorder that occurs mainly in women, and produceslight-brown symmetric areas of pigmentation on both sides of the faceunaccompanied by inflammation. The cause of the disorder has not yetbeen fully elucidated, however melasma may develop primarily due topolyendrocrine abnormalities by estrogen, adrenal cortex hormone, ACTH,etc., in association with sunlight irradiation, pregnancy, dysfunctionof the ovaries, the taking of oral contraceptives, the taking ofantiepileptics, etc.

Conventionally, melasma is treated by methods for eliminating endogenousand exogenous causes of the disorder by (1) oral administration ofvitamin C or a reduced glutathione agent, (2) elimination of causativeagents such as drugs, etc., and (3) avoidance of sunlight irradiation byuse of sunscreen (Hyojun Hifukagaku, 4th edition, pp 212-213, edited byYoshio SATO, issued by Igaku-Shoin). However, the conventional treatmentmethods do not produce satisfactory effects and are thus unsatisfactory.

Skin dullness is a serious aesthetic problem particularly for women andspecifically denotes skin conditions such as loss of skin clarity, skinmuddiness due to body waste accumulation, and uneven skin color. Skindullness may be caused by a combination of various factors, such as skinmuddiness or skin shading due to a thickened horny cell layeraccompanied by aging, reduced flushness in the skin, pigmentation,lowered skin resilience, yellowing of the skin, dirt such as sweat andsebum, etc.

As described above, since skin dullness is caused by the involvement ofvarious factors, skin dullness cannot be effectively reduced even bysubstances that have been considered as useful for removing chloasma.Various substances useful for reducing skin dullness have been examinedto date, however, at the present time, a substance that cansatisfactorily reduce skin dullness has not developed.

It has been reported that purine nucleic acid-related substances exhibitvarious physiological functions, however it is not known that suchsubstances can improve melasma and reduce skin dullness.

It is known that purine nucleic acid-related substances are hard toformulate. When the substance concerned is blended in a composition tobe a concentration such that its effects can be exhibited, the preparedcomposition is inferior in feeling of use, stability, etc. Inparticular, the substance is very difficult to add it into an emulsiondue to its property of reducing the strength of membranes formed at theoil-water interfaces. Therefore, in order to formulate the substanceinto an emulsion, such as a milky lotion or cream, it is necessary todevelop a method for improve the stability of the emulsion.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a composition that caneffectively improve melasma, and a composition in the form of an O/Wemulsion with favorable emulsification stability that can effectivelyimprove melasma. Another object of the present invention is to provide amethod for effectively improving melasma.

A further object of the invention is to provide a composition that caneffectively reduce skin dullness, and a composition in the form of anO/W emulsion with favorable emulsification stability that caneffectively reduce skin dullness. Another object of the presentinvention is to provide a method for effectively reducing skin dullness.

The present inventors carried out intensive research to solve theabove-described problems, and found that purine nucleic acid-relatedsubstances present in the living body, in particular adenosinemonophosphates, i.e., a monophosphoric acid ester of adenosine, or saltsthereof are excellent at improving melasma and reducing skin dullness.Further, the inventors found that an excellent emulsification stabilitycan be given to such purine nucleic acid-related substances, whichhitherto have been difficult to emulsify without losing the effectsthereof, by preparing an O/W emulsion by blending the above-mentionedpurine nucleic acid-related substance with a polyglyceryl fatty acidester, an alkanoyl lactic acid or salts thereof, an acrylic acid-alkylmethacrylate copolymer, water, and an oily component. The inventorsconducted further research and accomplished the present invention basedon these findings.

More specifically, the present invention relates to the followingcompositions for improving melasma:

-   Item 1. A composition for improving melasma comprising a purine    nucleic acid-related substance and a pharmaceutically or    cosmetically acceptable carrier.-   Item 2. A composition for improving melasma according to Item 1,    wherein the purine nucleic acid-related substance is an adenosine    monophosphate or a salt thereof.-   Item 3. A composition for improving melasma according to Item 1 or    2, comprising the purine nucleic acid-related substance in a    proportion of at least 0.01 wt. % based on the total amount of the    composition.-   Item 4. A composition for improving melasma according to any one of    Items 1 to 3, comprising the purine nucleic acid-related substance    in a proportion of 1 to 10 wt. % based on the total amount of a    composition.-   Item 5. A composition for improving melasma according to any one of    Items 1 to 4, wherein the composition has a pH in the range of 2 to    8.-   Item 6. A composition for improving melasma according to any one of    Items 1 to 5 used for an externally-applied medical or quasi-medical    drug, or a cosmetic.-   Item 7. A composition for improving melasma according to any one of    Items 1 to 6, wherein the composition further comprises a    polyglyceryl fatty acid ester, an alkanoyl lactic acid or a salt    thereof, an acrylic acid-alkyl methacrylate copolymer, water, and an    oil, and is formulated into an O/W-type emulsification.-   Item 8. A composition for improving melasma according to Item 7,    further comprising a polyhydric alcohol.-   Item 9. A composition for improving melasma according to Item 7 or    8, wherein the polyglyceryl fatty acid ester is an ester of a C₁₂₋₃₆    fatty acid and a polyglycerol having a polymerization degree of 6 or    more.-   Item 10. A composition for improving melasma according to any one of    Items 7 to 9, wherein the alkanoyl lactic acid comprises an alkanoyl    group having 8 or more carbons.-   Item 11. A composition for improving melasma according to any one of    Items 7 to 10, wherein the acrylic acid-alkylmethacrylate copolymer    comprises a C₅₋₄₀ alkyl group.-   Item 12. A composition for improving melasma according to any one of    Items 7 to 11, wherein the oil is a hydrocarbon liquid oil.-   Item 13. A composition for improving melasma according to any one of    Items 7 to 12, wherein the polyglyceryl fatty acid ester is an ester    of a C₁₂₋₃₆ fatty acid and a polyglycerol having a polymerization    degree of 6 or more, the alkanoyl alkanoyl lactic acid comprises an    alkanoyl group having 8 or more carbons, the acrylic acid-alkyl    methacrylate copolymer comprises a C₅₋₄₀ alkyl group, and the oil is    a hydrocarbon liquid oil.-   Item 14. A composition for improving melasma according to Item 8,    wherein the polyglyceryl fatty acid ester is included in a    proportion of 0.05 to 6 wt. %, the alkanoyl alkanoyl lactic acid or    a salt thereof is included in a proportion of 0.01 to 1 wt. %, the    acrylic acid-alkyl methacrylate copolymer is included in a    proportion of 0.01 to 0.8 wt. %, the oil is included in a proportion    of 0.3 to 20 wt. %, the polyhydric alcohol is included in a    proportion of 0.05 to 15 wt. %, and water is included in a    proportion of 50 to 90 wt. %, based on the total amount of the    composition.-   Item 15. A composition for improving melasma according to any one of    Items 7 to 14, wherein the polyglyceryl fatty acid ester and the    alkanoyl alkanoyl lactic acid or a salt thereof are included in a    weight ratio of 95:5 to 60:40.-   Item 16. A composition for improving melasma according to any one of    Items 7 to 15, further comprising a lower alcohol.

The present invention also relates to the following compositions forreducing skin dullness:

-   Item 17. A composition for reducing skin dullness comprising a    purine nucleic acid-related substance, and a pharmaceutically or    cosmetically acceptable carrier.-   Item 18. A composition for reducing skin dullness according to Item    17, wherein the purine nucleic acid-related substance is an    adenosine monophosphate or a salt thereof.-   Item 19. A composition for reducing skin dullness according to Item    17 or 18, comprising the purine nucleic acid-related substance in a    proportion of at least 0.01 wt. % based on the total amount of the    composition.-   Item 20. A composition for reducing skin dullness according to any    one of Items 17 to 19, comprising the purine nucleic acid-related    substance in a proportion of 1 to 10 wt. % based on the total amount    of the composition.-   Item 21. A composition for reducing skin dullness according to any    one of Items 17 to 20, wherein the composition has a pH in the range    of 2 to 8.-   Item 22. A composition for reducing skin dullness according to any    one of Items 17 to 21 used for an externally-applied medical or    quasi-medical drug, or a cosmetic.-   Item 23. A composition for reducing skin dullness according to any    one of Items 17 to 22, wherein the composition further comprises a    polyglyceryl fatty acid ester, an alkanoyl alkanoyl lactic acid or a    salt thereof, an acrylic acid-alkyl methacrylate copolymer, water,    and an oil, and is formulated into an O/W-type emulsification.-   Item 24. A composition for reducing skin dullness according to Item    23, further comprising a polyhydric alcohol.-   Item 25. A composition for reducing skin dullness according to Item    23 or 24, wherein the polyglyceryl fatty acid ester is an ester of a    C₁₂₋₃₆ fatty acid and a polyglycerol having a polymerization degree    of 6 or more.-   Item 26. A composition for reducing skin dullness according to any    one of Items 23 to 25, wherein the alkanoyl alkanoyl lactic acid    comprises an alkanoyl group having 8 or more carbons.-   Item 27. A composition for reducing skin dullness according to any    one of Items 23 to 26, wherein the acrylic acid-alkyl methacrylate    copolymer comprises a C₅₋₄₀ alkyl group.-   Item 28. A composition for reducing skin dullness according to any    one of Items 23 to 27, wherein the oil is a hydrocarbon liquid oil.-   Item 29. A composition for reducing skin dullness according to Item    23, wherein the polyglyceryl fatty acid ester is an ester of a    C₁₂₋₃₆ fatty acid and a polyglycerol having a polymerization degree    of 6 or more, the alkanoyl alkanoyl lactic acid comprises an    alkanoyl group having 8 or more carbons, the acrylic acid-alkyl    methacrylate copolymer comprises a C₅₋₄₀ alkyl group, and the oil is    a hydrocarbon liquid oil.-   Item 30. A composition for reducing skin dullness according to Item    24, wherein the polyglyceryl fatty acid ester is included in a    proportion of 0.05 to 6 wt. %, the alkanoyl alkanoyl lactic acid or    a salt thereof is included in a proportion of 0.01 to 1 wt. %, the    acrylic acid-alkyl methacrylate copolymer is included in a    proportion of 0.01 to 0.8 wt. %, the oil is included in a proportion    of 0.3 to 20 wt. %, the polyhydric alcohol is included in a    proportion of 0.05 to 15 wt. %, and water is included in a    proportion of 50 to 90 wt. %, based on the total amount of the    composition.-   Item 31. A composition for reducing skin dullness according to any    one of Items 23 to 30, wherein the polyglyceryl fatty acid ester and    the alkanoyl alkanoyl lactic acid or a salt thereof are included in    a weight ratio of 95:5 to 60:40.-   Item 32. A composition for reducing skin dullness according to any    one of Items 23 to 31, further comprising a lower alcohol.

The present invention further relates to the following methods forimproving melasma:

-   Item 33. A method for improving melasma, comprising applying a    purine nucleic acid-related substance to a melasma lesion.-   Item 34. A method for improving melasma according to Item 33,    wherein the purine nucleic acid-related substance is an adenosine    monophosphate or a salt thereof.-   Item 35. A method for improving melasma according to Item 33 or 34,    comprising applying a composition comprising the purine nucleic    acid-related substance in a proportion of at least 0.01 wt. % based    on the total amount of the composition to the melasma lesion.-   Item 36. A method for improving melasma according to Item 33 or 34,    comprising applying a composition comprising the purine nucleic    acid-related substance in a proportion of 1 to 10 wt. % based on the    total amount of the composition to the melasma lesion.-   Item 37. A method for improving melasma according to Item 35 or 36,    wherein the composition has a pH in the range of 2 to 8.-   Item 38. A method for improving melasma according to any one of    Items 35 to 37, wherein the composition is used for an    externally-applied medical or quasi-medical drug, or a cosmetic.-   Item 39. A method for improving melasma according to any one of    Items 35 to 38, wherein the composition further comprises a    polyglyceryl fatty acid ester, an alkanoyl lactic acid or a salt    thereof, an acrylic acid-alkyl methacrylate copolymer, water, and an    oil, and is formulated into an O/W-type emulsification.-   Item 40. A method for improving melasma according to Item 39,    wherein the composition further comprises a polyhydric alcohol.-   Item 41. A method for improving melasma according to Item 39 or 40,    wherein the polyglyceryl fatty acid ester is an ester of a C₁₂₋₃₆    fatty acid and a polyglycerol having a polymerization degree of 6 or    more.-   Item 42. A method for improving melasma according to any one of    Items 39 to 41, wherein the alkanoyl lactic acid comprises an    alkanoyl group having 8 or more carbons.-   Item 43. A method for improving melasma according to any one of    Items 39 to 42, wherein the acrylic acid-alkyl methacrylate    copolymer comprises a C₅₋₄₀ alkyl group.-   Item 44. A method for improving melasma according to any one of    Items 39 to 43, wherein the oil is a hydrocarbon liquid oil.-   Item 45. A method for improving melasma according to Item 39,    wherein the polyglyceryl fatty acid ester is an ester of a C₁₂₋₃₆    fatty acid and a polyglycerol having a polymerization degree of 6 or    more, the alkanoyl lactic acid comprises an alkanoyl group having 8    or more carbons, the acrylic acid-alkyl methacrylate copolymer    comprises a C₅₋₄₀ alkyl group, and the oil is a hydrocarbon liquid    oil.-   Item 46. A method for improving melasma according to Item 40,    wherein the composition comprises the polyglyceryl fatty acid ester    in a proportion of 0.05 to 6 wt. %, the alkanoyl lactic acid or a    salt thereof in a proportion of 0.01 to 1 wt. %, the acrylic    acid-alkyl methacrylate copolymer in a proportion of 0.01 to 0.8 wt.    %, the oil in a proportion of 0.3 to 20 wt. %, the polyhydric    alcohol in a proportion of 0.05 to 15 wt. %, and water in a    proportion of 50 to 90 wt. %, based on the total amount of the    composition.-   Item 47. A method for improving melasma according to any one of    Items 39 to 46, wherein the composition comprises the polyglyceryl    fatty acid ester and the alkanoyl lactic acid or a salt thereof in a    weight ratio of 95:5 to 60:40.-   Item 48. A method for improving melasma according to any one of    Items 39 to 47, wherein the composition further comprises a lower    alcohol.

The present invention further relates to the following methods forreducing skin dullness:

-   Item 49. A method for reducing skin dullness, comprising applying a    purine nucleic acid-related substance to a dullness region of the    skin.-   Item 50. A method for reducing skin dullness according to Item 49,    wherein the purine nucleic acid-related substance is an adenosine    monophosphate or a salt thereof.-   Item 51. A method for reducing skin dullness according to Item 49 or    50, comprising applying a composition comprising the purine nucleic    acid-related substance in a proportion of at least 0.01 wt. % based    on the total amount of the composition to the dullness region of the    skin.-   Item 52. A method for reducing skin dullness according to Item 49 or    50, comprising applying a composition comprising the purine nucleic    acid-related substance in a proportion of 1 to 10 wt. % based on the    total amount of the composition to the dullness region of the skin.-   Item 53. A method for reducing skin dullness according to Item 51 or    52, wherein the composition has a pH in the range of 2 to 8.-   Item 54. A method for reducing skin dullness according to any one of    Items 51 to 53, wherein the composition is used for an    externally-applied medical or quasi-medical drug, or a cosmetic.-   Item 55. A method for reducing skin dullness according to any one of    Items 51 to 54, wherein the composition further comprises a    polyglyceryl fatty acid ester, an alkanoyl lactic acid or a salt    thereof, an acrylic acid-alkyl methacrylate copolymer, water, and an    oil, and is formulated into an O/W-type emulsification.-   Item 56. A method for reducing skin dullness according to Item 55,    wherein the composition further comprises a polyhydric alcohol.-   Item 57. A method for reducing skin dullness according to Item 55 or    56, wherein the polyglyceryl fatty acid ester is an ester of a    C₁₂₋₃₆ fatty acid and a polyglycerol having a polymerization degree    of 6 or more.-   Item 58. A method for reducing skin dullness according to any one of    Items 55 to 57, wherein the alkanoyl lactic acid comprises an    alkanoyl group having 8 or more carbons.-   Item 59. A method for reducing skin dullness according to any one of    Items 55 to 58, wherein the acrylic acid-alkyl methacrylate    copolymer comprises a C₅₋₄₀ alkyl group.-   Item 60. A method for reducing skin dullness according to any one of    Items 55 to 59, wherein the oil is a hydrocarbon liquid oil.-   Item 61. A method for reducing skin dullness according to any one of    Items 55 to 60, wherein the polyglyceryl fatty acid ester is an    ester of a C₁₂₋₃₆ fatty acid and a polyglycerol having a    polymerization degree of 6 or more, the alkanoyl lactic acid    comprises an alkanoyl group having 8 or more carbons, the acrylic    acid-alkyl methacrylate copolymer comprises a C₅₋₄₀ alkyl group, and    the oil is a hydrocarbon liquid oil.-   Item 62. A method for reducing skin dullness according to Item 56,    wherein the composition comprises the polyglyceryl fatty acid ester    in a proportion of 0.05 to 6 wt. %, the alkanoyl lactic acid or a    salt thereof in a proportion of 0.01 to 1 wt. %, the acrylic    acid-alkyl methacrylate copolymer in a proportion of 0.01 to 0.8 wt.    %, the oil in a proportion of 0.3 to 20 wt. %, the polyhydric    alcohol in a proportion of 0.05 to 15 wt. %, and water in a    proportion of 50 to 90 wt. %, based on the total amount of the    composition.-   Item 63. A method for reducing skin dullness according to any one of    Items 55 to 62, wherein the composition comprises the polyglyceryl    fatty acid ester and the alkanoyl lactic acid or a salt thereof in a    weight ratio of 95:5 to 60:40.-   Item 64. A method for reducing skin dullness according to any one of    Items 55 to 63, wherein the composition further comprises a lower    alcohol.

The present invention also relates to the following modes of embodiment:

-   Item 65. Use of a purine nucleic acid-related substance for    preparing a composition for improving melasma.-   Item 66. Use of a purine nucleic acid-related substance for reducing    skin dullness.-   Item 67. Use of a purine nucleic acid-related substance for    improving melasma.-   Item 68. Use of a purine nucleic acid-related substance for reducing    skin dullness.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the mean average of the variation, ΔL* of an L* valueindicating skin lightness of the skin, the mean average of thevariation, Δa* of an a* value indicating redness of the skin, thevariation, Δb* of an b* value indicating yellowness of the skin, and thevariation, ΔE*ab of color difference of the skin, E*ab, 4, 8, 12, and 16weeks after initiation of the application of the composition as comparedto the L* value, the a* value and the b* value of the skin of thesubjects before initiation of the application of the composition.

BEST MODE FOR CARRYING OUT THE INVENTION

(1) A Composition for Improving Melasma

The composition for improving melasma of the present invention comprisesa purine nucleic acid-related substance and a pharmaceutically orcosmetically acceptable carrier.

The purine nucleic acid-related substances used in the invention, whichmay be hereinafter referred to as a purine base, denotes a purine orvarious purine derivatives having a purine nucleus as a skeleton, andsalts thereof. Purine nucleic acid-related substances usable in theinvention are not restricted insofar as the effect of improving melasmais exhibited when applied to the skin. Any purine nucleic acid-relatedsubstances that can be incorporated into cosmetics, externally-appliedmedical and quasi-medical drugs may be used without limitation. Thosethat are water soluble or hydrophilic are preferable. Examples of purinebases include adenine, guanine, hypoxanthine, xanthine, adenosine,guanosine, inosine, adenosine phosphates [adenosine 2′-monophosphate,adenosine 3′-monophosphate, adenosine 5′-monophosphate (AMP), cyclicadenosine 3′5′-monophosphate (cAMP), adenosine 5′-diphosphate (ADP),adenosine 5′-triphosphate (ATP)], guanosine phosphates (guanosine3′-monophosphate, guanosine 5′-monophosphate, guanosine 5′-diphosphate,guanosine 5′-triphosphate), adenylosuccinic acid, xanthylic acid,inosinic acid, flavine adenine dinucleotide (FAD), nicotinamide adeninedinucleotide (NAD) and the like. Preferable among these are adenine,guanine, adenosine monophosphates (adenosine 2′-monophosphate, adenosine3′-monophosphate, AMP, and cAMP), ADP, ATP, FAD and NAD. Preferableamong the above are adenosine monophosphates, and particularlypreferably AMP.

In the invention, purine base salts can be used in place of or incombination with purine bases. Examples of such purine base saltsinclude alkali metal salts such as sodium salts and potassium salts;alkaline earth metal salts such as calcium salts, magnesium salts, andbarium salts; salts of basic amino acids such as arginine and lysine;salts of ammoniums such as ammonium, tricyclohexylammonium salts; andsalts of alkanolamines such as monoethanolamine, diethanolamine,triethanolamine, monoisopropanolamine, diisopropanolamine andtriisopropanolamine. Alkali metal salts of purine bases are preferable.Monosodium adenosine monophosphate and disodium adenosine monophosphateare particularly preferable.

Purine nucleic acid-related substances can be used singly or incombination of two species or more. The manner of combination is notparticularly restricted insofar as it does not impair the effects of theinvention.

Any pharmaceutically or cosmetically acceptable carriers can be usedwithout limitation for the composition for improving melasma of theinvention. Examples of such carriers include water, oils, etc. Specificexamples of such water types and oils are the same as the substances forpreparing an emulsion composition described later. Such pharmaceuticallyor cosmetically acceptable carriers may be used singly or incombination.

The proportion of purine nucleic acid-related substances incorporatedinto the composition for improving melasma of the invention can bedetermined according to the form, the target, the desired effects or thelike of the composition. More specifically, 0.01 wt. % can be mentionedas a lower limit of the proportion for incorporating the purine nucleicacid-related substances, based on the total amount of the compositionfor improving melasma. The upper limit thereof is not limited in view ofthe effects of the invention, and may be within the range that isacceptable for preparing the composition. For instance, 10 wt. % can bementioned as an upper limit of the proportion for incorporating thepurine nucleic acid-related substances based on the total amount of thecomposition. Preferable examples of the proportion for incorporating thepurine nucleic acid-related substances include 0.01 to 10 wt. %, morepreferably 1 to 10 wt. %, and especially preferably 3 to 6 wt. %, basedon the total amount of the composition. The effect of improving melasmatends to be reduced when the proportion is much lower than 0.01 wt. %.

The composition for improving melasma of the invention may contain, asrequired, a wide variety of additives typically incorporated intoexternally-applied preparations, such as externally-applied medical orquasi-medical drugs, or cosmetics. Examples of such additives includesurfactants, solubilizing components, emulsifiers, colorants (dyes,pigments), aromatic substances, antiseptics, bactericides, thickeners,antioxidants, sequestrants, pH adjusters, and deodorizers. Suchcomponents can be used singly or in combination of two species or more.

The composition for improving melasma of the invention may furthercontain various medicinal agents such as humectants, UV absorbers,whiteners, UV dispersants, vitamins, plant extracts, astringents,anti-inflammatory agents, cell activators, etc. Such components can beused singly or in combination of two species or more.

The composition for improving melasma of the invention can be made intovarious desired forms such as liquids, an oil, lotions, liniments,emulsions, suspensions, creams, ointments, sheets, aerosols, sprays,sticks and the like.

In particular, the composition for improving melasma of the invention ispreferably formulated into emulsion compositions such as emulsions,creams, etc. in the form of an O/W emulsion composition as describedbelow. In the O/W emulsion composition, the composition for improvingmelasma of the invention can be formulated into a stable emulsion formwithout separation, oil floating, etc., and in addition, the purinenucleic acid-related substance can effectively improve melasma.

The O/W emulsion composition can be prepared by blending and emulsifyinga polyglyceryl fatty acid ester, an alkanoyl lactic acid or a saltthereof, an acrylic acid-alkyl methacrylate copolymer, water, and an oilwith the above-mentioned purine nucleic acid-related substance.

Polyglyceryl fatty acid esters usable in the present invention are notlimited. Examples include esters of a C12-36 fatty acid and apolyglycerol having a polymerization degree of 6 or more, especially 6to 10. Fatty acids that form esters with polyglycerols includesaturated, unsaturated, linear and branched fatty acids. Specificexamples are capric acid, lauric acid, isotridecanoic acid, myristicacid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid,oleic acid, linoleic acid, behenic acid, ricinolic acid, and the like.

Specific examples of polyglyceryl fatty acid esters are hexaglycerolmonolaurate, hexaglycerol monoisostearate, hexaglycerol monomyristate,hexaglycerol dioleate, hexaglycerol dimyristate, hexaglyceroldipalmitate, hexaglycerol distearate, hexaglycerol dibehenylate,hexaglycerol trilaurate, hexaglycerol trimyristate, hexaglyceroltripalmitate, hexaglycerol tristearate, hexaglycerol tribehenylate,hexaglycerol tetralaurate, hexaglycerol tetramyristate, hexaglyceroltetrapalmitate, hexaglycerol tetrastearate, hexaglyceroltetrabehenylate, hexaglycerol pentalaurate, hexaglycerol pentamyristate,hexaglycerol pentapalmitate, hexaglycerol pentastearate, hexaglycerolpentabehenylate, decaglyceryl monocaprate, decaglyceryl monolaurate,decaglyceryl monomyristate, decaglyceryl monopalmitate, decaglycerylmonostearate, decaglyceryl monooleate, decaglyceryl monolinoleate,decaglyceryl monoisostearate, decaglyceryl dicaprate, decaglyceryldilaurate, decaglyceryl dimyristate, decaglyceryl dipalmitate,decaglyceryl distearate, decaglyceryl diisostearate, decaglyceryltrilaurate, decaglyceryl trimyristate, decaglyceryl tripalmitate,decaglyceryl tristearate, decaglyceryl trioleate, decaglyceryltribehenylate, decaglyceryl pentastearate, decaglyceryl pentaoleate,decaglyceryl pentaisostearate, decaglyceryl heptastearate, decaglyceryldecastearate, decaglyceryl decaoleate, decaglyceryl decaisostearate, andthe like. However, the polyglyceryl fatty acid esters are not limitedthereto.

Such polyglyceryl fatty acid estersmaybe used singly or in combination.Polyglyceryl fatty acid esters having an HLB value of 10 or more,especially 10 to 15, can be suitably used. It is preferable to use thepolyglyceryl fatty acid ester in a proportion of 0.05 to 6 wt. % basedon the total amount of the composition for improving melasma, morepreferably in a proportion of 0.1 to 5.5 wt. %.

Alkanoyl lactic acids usable in the invention are not limited. Examplesinclude alkanoyl lactic acids having an alkanoyl group with 8 or morecarbons, preferably alkanoyl lactic acids having a C₈₋₁₈ alkanoyl group.Specific examples include octanoyl lactic acid, caproyl lactic acid,2-ethyl hexanoyl lactic acid, lauroyl lactic acid, myristoyl lacticacid, palmitoyl lactic acid, stearoyl lactic acid, isostearoyl lacticacid, oleoyl lactic acid, 12-hydroxystearoyl lactic acid, linoleyllactic acid, and behenoyl lactic acid. Preferable are stearoyl lacticacid and isostearoyl lactic acid. Such alkanoyl lactic acids can be usedin the form of salts. Examples of such salts include sodium salts,potassium salts, and like alkali metal salts; ammonium salts,triethanolamine salts, and the like. Preferred are sodium salts, morespecifically, sodium stearoyl lactate and sodium isostearoyl lactate.Such alkanoyl lactic acids and salts thereof may be used singly or incombination. It is preferable to use the alkanoyl lactic acid or a saltthereof in a proportion of 0.01 to 1 wt. % based on the total amount ofthe composition for improving melasma, more preferably in a proportionof 0.1 to 0.5 wt. %.

The proportion for blending the polyglyceryl fatty acid ester with thealkanoyl lactic acid or a salt thereof is desirably such that the HLBvalue of the mixture be 10 or more, preferably 10 to 13. Specificexamples of the proportion for blending the polyglyceryl fatty acidester with the alkanoyl lactic acid or a salt thereof are weight ratiosof 95:5 to 60:40, preferably 90:10 to 70:30.

Acrylic acid-alkyl methacrylate copolymers usable in the invention arenot limited. Typical examples usually include those having an alkylchain with 5 to 40 carbons. Preferred are those having an alkyl chainwith 10 to 30 carbons. Although not limited thereto, such polymers arecommercially available, for example, from Noveon Inc. under thetrademarks of Carbopol and Pemulen, such as Carbopol 1342, Pemulen TR-1,and Pemulen TR-2. Such acrylic acid-alkyl methacrylate copolymers may beused singly or in combination. It is preferable to use the acrylicacid-alkylmethacrylate copolymer in a proportion of 0.01 to 0.8 wt. %based on the total amount of the composition for improving melasma, morepreferably in a proportion of 0.3 to 0.6 wt. %, still more preferably ina proportion of 0.4 to 0.6 wt. %.

Any types of water can be used without limitation insofar as they arepharmaceutically or cosmetically acceptable. For instance, distilledwater, ion-exchanged water, sterilized water, or electrolyte-containingwater can be used as the water ingredient. Examples ofelectrolyte-containing water include sea water, hot-spring water,mineral water, and the like. The term “sea water” herein refers tosurface sea water, intermediate sea water, deep sea water, and ultradeep sea water. The proportion of the water included in the compositionfor improving melasma is not limited. Usually, it is suitably selectedfrom a range of 50 to 90 wt. %. Preferably, it is selected from a rangeof 60 to 80 wt. %.

Oils usable in the invention are not limited. Specific examples includepeanut oil, sesame oil, soybean oil, safflower oil, avocado oil,sunflower oil, corn oil, rapeseed oil, cottonseed oil, castor oil,camellia oil, coconut oil, olive oil, poppy oil, cacao oil, jojoba oil,and like vegetable oils; beef tallow, lard, lanolin, and like animaloils and fats; petrolatum, liquid paraffin, squalane, α-olefinoligomers, and like hydrocarbon liquid oils; isopropyl myristate,isopropyl isostearate, myristyl myristate, cetyl palmitate, cetylisooctate, isocetyl myristate, n-butyl myristate, octyldodecylmyristate, isopropyl linolenate, propyl ricinoleate, isopropylricinoleate, isobutyl ricinoleate, heptyl ricinoleate, diethyl sebacate,diisopropyl adipate, and like higher fatty acid esters; white beeswax,whale wax, Japan wax, and like waxes; cetyl alcohol, stearyl alcohol,behenyl alcohol, batyl alcohol, chimyl alcohol, and like higheraliphatic alcohols; waxes; stearic acid, oleic acid, palmitic acid, andlike higher fatty acids; mono-, di-, or triglyceride mixtures of C₁₂₋₁₈saturated or unsaturated fatty acids; methyl polysiloxane, dimethylpolysiloxane, methylphenyl polysiloxane, methyl hydrogen polysiloxane,and like linear silicones; decamethylcyclopentasiloxane,octamethylcyclotetrasiloxane, methylcyclosiloxane, and like cyclicsilicones; crosslinked methyl polysiloxane, crosslinked methylphenylpolysiloxane, and like crosslinked silicones; and, for example, siliconeoils such as silicones modified by polyoxyethylene, polyoxypropylene orthe like; in addition to others. Preferable are hydrocarbon liquid oilssuch as vaseline, liquid paraffin, squalane, α-olefin oligomer, and thelike. Such oils may be used singly or in combination. When oils aresolid, it is preferable to liquefy them by means of an auxiliaryresolvent before use. It is preferable to use the oil in a proportion of0.3 to 20 wt. % based on the total amount of the composition forimproving melasma, more preferably in a proportion of 0.5 to 15 wt. %.

Although the preparation method for the composition for improvingmelasma in the form of an O/W emulsion composition is not limited, it ispreferable to prepare it according to the method described below:

-   (1) The polyglyceryl fatty acid ester and the alkanoyl lactic acid    or a salt thereof are mixed with the oil and preferably with a    polyhydric alcohol. The mixture is stirred while being heated. After    the mixture is uniformly dissolved, it is cooled to give a    nonaqueous emulsion.-   (2) The nonaqueous emulsion thus obtained is blended with an aqueous    solution (aqueous composition) that is separately prepared and    contains the purine nucleic acid-related subusutance, water and the    acrylic acid-alkyl methacrylate copolymer. The composition for    improving melasma in the form of an O/W emulsion is then prepared    according to a conventional method.

It is preferable to use the polyhydric alcohol in Process (1) forpreparing the nonaqueous emulsion in order to further improve thedevelopment of the emulsifying ability of the polyglyceryl fatty acidester, the alkanoyl lactic acid, etc.

Polyhydric alcohols usable herein are not limited. Specific examplesinclude polyglycerols having a polymerization degree of 2 to 10 (forexample, diglycerol, triglycerol, tetraglycerol, etc.), ethylene glycol,diethylene glycol, polyethylene glycol, 1,3-butylene glycol, propyleneglycol, dipropylene glycol, isoprene glycol, pentadiol, sorbitol,maltitol, fructose, and the like. The use of glycerol is preferable.Such polyhydric alcohols may be used singly or in combination. Whenused, the polyhydric alcohol is used in a proportion of 0.05 to 15 wt. %based on the total amount of the composition for improving melasma,preferably in a proportion of 3 to 10 wt. %.

In Process (2), which is for emulsification, a lower alcohol can beincorporated in addition to the electrolyte, water, and the acrylicacid-alkyl methacrylate copolymer in the aqueous solution (aqueouscomposition) that is to be blended with the nonaqueous emulsion. Thisenhances the percutaneous absorption of the purine nucleic acid-relatedsubstance. Lower alcohols usable in the invention are not limited, butare usually suitably selected from alcohols having 1 to 6 carbons.Preferable examples are ethanol, propanol, isopropanol, and like C₁₋₄alcohols. Such lower alcohols may be used singly or in combination. Theuse of ethanol is preferable. When used, the lower alcohol is used in aproportion of 0.5 to 15 wt. % based on the total amount of thecomposition for improving melasma, preferably in a proportion of 3 to 10wt. %.

Moreover, a polyhydric alcohol can be used in the aqueous solutiondescribed above (aqueous composition). The use thereby makes it possibleto control the moisturizing ability and sensory characteristics of thecomposition for improving melasma to the desired degree. Polyhydricalcohols usable in the aqueous solution include those identified above.When a polyhydric alcohol is used in the preparation of a nonaqueousemulsion, it is preferable to use polyhydric alcohols that are identicalor highly compatible with those for the aqueous solution.

Examples of the method for emulsifying the mixture of the nonaqueousemulsion and the aqueous solution (aqueous composition) include stirringthe mixture under atmospheric pressure or high pressure using ahomomixer. The particles of the resulting emulsion can be furtherrefined by a homogenizer as required.

The proportion of the nonaqueous emulsion to the aqueous solution(aqueous composition) is not limited. It is usually desirable to controlthe proportion of the nonaqueous emulsion to 1 to 40 wt. %, preferably 1to 30 wt. %, based on the total amount of the composition for improvingmelasma, to thereby give a composition for improving melasma in the formof a more stable O/W emulsion composition.

The viscosity of the composition for improving melasma of the inventionin the form of the O/W emulsion composition is not limited. It isusually desirable to prepare the O/W emulsion composition to have aviscosity of 30000 cps or less, preferably 500 to 20000 cps, at atemperature of 20° C. (Viscometer: B-type viscometer, Rotor: No. 1 to 4,Rotation rate: 6, 12, 30, or 60 rpm).

The above-described composition for improving melasma of the inventionexerts the effect of improving melasma, when applied in the form of theexternally-applied compositions to a melasma lesion, due to the effectof the purine nucleic acid-related substances included in thecomposition. Accordingly, the composition for improving melasma of thepresent invention can be formulated into externally-applied compositionssuch as an externally-applied medical or quasi-medical drug, a cosmetic,etc. The composition for improving melasma of the invention is notlimited in purpose; specific purposes include externally-applied medicaldrugs, externally-applied quasi-medical drugs; makeup cosmetics such asfoundations, rouges, mascaras, eye shadows, eyeliners, face powders, lipsticks, etc; basic skin care products such as emulsions, creams,lotions, oils and packs; washes such as facial washes, cleansing creamsand body washes; cleaning agents; cleaners; bath agents, etc.

The composition for improving melasma of the invention usually has a pHin the range of 2 to 8. In view of low irritation to the skin and mucosaand pleasant skin feeling upon use, it is preferable to have a pH in therange of 2 to 7, more preferably 3 to 7, and further more preferably aweakly acidic pH of 5 to neutral pH of 7.

The composition for improving melasma of the invention can exert theeffect of improving melasma by being attached, sprayed or directlyapplied to a melasma lesion of the skin. The amount and frequency ofapplication of the composition for improving melasma may be determinedaccording to the types and concentrations of the purine nucleicacid-related substances used, the age of the user, the gender, thecondition of the affected part of the skin, the application form, theeffect intended, etc. The composition for improving melasma of theinvention may be applied to the melasma lesion in a suitable amount onceor several times per day.

As described above, purine nucleic acid-related substances have theeffect of improving melasma. Therefore, the present invention providesthe use of purine nucleic acid-related substances for the production ofa composition for improving melasma.

(2) A Composition for Reducing Skin Dullness

The composition for reducing skin dullness of the present inventioncomprises a purine nucleic acid-related substance, and apharmaceutically or cosmetically acceptable carrier.

The composition for reducing skin dullness of the invention can containpurine nucleic acid-related substances or pharmaceutically orcosmetically acceptable carriers that are the same as those used in theabove composition for improving melasma.

The proportion for incorporating the purine nucleic acid-relatedsubstances into the composition for reducing skin dullness, the widevariety of additives or medicinal properties that can be added to thecomposition, the form of the composition, and the pH thereof are thesame as those in the above-described composition for improving melasma.

In particular, it is preferable to formulate the composition forreducing skin dullness into emulsion compositions such as emulsions,creams, or the like by blending and emulsifying a polyglyceryl fattyacid ester, alkanoyl lactic acid or a salt thereof, an acrylicacid-alkyl methacrylate copolymer, water, and an oil with a purinenucleic acid-related substance. More preferably, the composition isprepared by further blending a polyhydric alcohol and/or a loweralcohol. The O/W emulsion composition for reducing skin dullness thusobtained is in a stable emulsified state without separation and oilfloating, and can effectively exhibit the effect of reducing skindullness. The type of polyglyceryl fatty acid esters, alkanoyl lacticacids or salts thereof, acrylic acid-alkyl methacrylate copolymers,water, oils, polyhydric alcohols and lower alcohols that are usable inthe O/W emulsion composition; amounts thereof; preparation methodsthereof; and viscosities thereof, are the same as those in thecomposition for improving melasma in the form of the O/W emulsioncomposition.

The composition for reducing skin dullness of the invention can exertthe effect of reducing skin dullness by being attached, sprayed, ordirectly applied to the dullness region of the skin. The amounts andfrequencies of application of the composition for improving melasma maybe determined according to the type of purine nucleic acid-relatedsubstances used, the concentrations thereof, the age of the user, thegender, the condition of the affected part of the skin, the applicationform, the effect intended, etc. The composition for reducing skindullness of the invention may be applied to the dullness region of theskin in a suitable amount once or several times per day.

As described above, purine nucleic acid-related substances have theeffect of reducing skin dullness. Therefore, the present inventionprovides the use of purine nucleic acid-related substances forproduction of a composition for reducing skin dullness.

(3) A Method for Improving Melasma

As described above, the purine nucleic acid-related substances caneffectively improve melasma. Thus, the present invention provides amethod for improving melasma using a purine nucleic acid-relatedsubstance.

The method for improving melasma of the present invention can be carriedout by applying a purine nucleic acid-related substance as such, or acomposition comprising the substance to a melasma lesion.

Purine nucleic acid-related substances usable in the method of theinvention are the same as used in the above composition for improvingmelasma.

In the method of the invention, the manner of applying the purinenucleic acid-related substance to the melasma lesion is not limitedinsofar as the purine nucleic acid-related substance is brought intocontact with the melasma legion. For example, the purine nucleicacid-related substance alone, or a composition comprising the substanceas an active ingredient and pharmaceutically or cosmetically acceptablebases, carriers, additives, or medicinal agents can be applied to themelasma lesion. More specifically, the substance or the compositioncomprising it is spread or sprayed onto the target skin portion, orattached to the skin in the form of a patch.

A method of applying the composition for improving melasma to a melasmalesion can be mentioned as a preferable embodiment of the presentinvention.

The amounts and frequencies of application of the purine nucleicacid-related substance to the lesion may be determined according to thetype of purine nucleic acid-related substances used, the age of theuser, the gender, the condition of melasma, the application form, theeffect intended, etc. The purine nucleic acid-related substance can beapplied to the melasma lesion of the skin in a suitable amount once orseveral times per day.

As described above, by the use of the purine nucleic acid-relatedsubstances, amelasma can be effectively improved. Therefore, the presentinvention also provides the use of purine nucleic acid-relatedsubstances for improving melasma.

(4) A Method for Reducing Skin Dullness

As described above, the purine nucleic acid-related substances caneffectively reduce skin dullness. Thus, the present invention provides amethod for reducing skin dullness using a purine nucleic acid-relatedsubstance.

The method for reducing skin dullness of the present invention can becarried out by applying a purine nucleic acid-related substance as such,or a composition comprising the substance to the dullness region of theskin.

Purine nucleic acid-related substances usable in the method of theinvention are the same as used in the above composition for reducingskin dullness.

In the method of the invention, the manner of applying the purinenucleic acid-related substance to the dullness region of the skin is notlimited insofar as the purine nucleic acid-related substance is broughtinto contact with the target part. For example, the purine nucleicacid-related substance alone, or a composition comprising the substanceas an active ingredient and pharmaceutically or cosmetically acceptablecarriers, additives, or medicinal agents can be applied to the dullnessregion of the skin. More specifically, the substance or the compositioncomprising it is spread or sprayed onto the target skin portion, orattached to the skin in the form of a patch.

A method of applying the composition for reducing skin dullness to adullness region of the skin can be mentioned as a preferable embodimentof the present invention.

The amounts and frequencies of application of the purine nucleicacid-related substances to the dullness region of the skin may bedetermined according to the type of purine nucleic acid-relatedsubstances used, the age of the user, the gender, the intended use, thecondition of the dullness region, the application form, etc. The purinenucleic acid-related substance can be applied to the dullness region ofthe skin in a suitable amount once or several times per day.

As described above, by the use of the purine nucleic acid-relatedsubstance, the skin dullness can be effectively reduced. Therefore, thepresent invention also provides the use of the purine nucleicacid-related substance for reducing skin dullness.

EXAMPLES

The present invention is described in more detail with reference to thefollowing examples, although the present invention is not limited tothese examples.

Example 1 Emulsions

(wt. %) Disodium adenosine 5′-monophosphate 3.0 Sodium isostearoyllactate 0.2 Acrylic acid-alkyl methacrylate copolymer 0.4 Light liquidparaffin 5.0 Glycerol 6.0 Ethanol 5.0 Antiseptic Suitable amountDecaglycerol monoisostearate 1.5 Decaglycerol monomyristate 0.3 pHAdjuster (pH 6.5) Pure water Balance 100.0 wt. %

An emulsion was produced by the method described below according to theabove formulation. The decaglycerol monoisostearate, decaglycerolmonomyristate, sodium isostearoyl lactate, glycerol, and lightliquid-paraffin were blended, dissolved while being heated, and cooled,to prepare a uniform nonaqueous emulsion. Mixed therewith was an aqueouscomposition (aqueous solution) that was separately prepared bydissolving in distilled water (pure water) the disodium adenosine5′-monophosphate, acrylic acid-alkyl methacrylate copolymer, ethanol,antiseptic agent and pH adjuster. The mixture was stirred by a homomixerto become an emulsion in an O/W-emulsified state.

Test Example 1 Melasma Improving Test

The following tests were conducted to evaluate the effect of improvingmelasma of a purine nucleic acid-related substance.

<Test Method>

A suitable amount (an amount that can be uniformly applied to an entireface: about five drops) of the emulsion prepared according to theformulation of Example 1 was applied over the entire face of 27 patientswith melasma, twice per day, after washing of the face, and this wascontinued for 16 weeks (except for one person who stopped by 12 weeks).Before initiation of the application, 4, 8, 12, and 16 weeks afterinitiation of the application, a dermatologist made an overallevaluation of the color intensity and the range of melasma, andclassified the condition of the melasma of each patient into fivegrades, “no melasma”, “slight”, “mild”, “moderate”, and “severe”,according to the criteria of the following table 1. TABLE 1 Range Ultra-Symptom None narrow Narrow Moderate Wide Color None None None None NoneNone intensity Slightly None Slight Slight Mild Moderate weak Weak NoneSlight Mild Moderate Moderate Moderate None Slight Mod- Severe Severeerate Strong None Mod- Mod- Severe Severe erate erate

The dermatologist-diagnosed melasma grades of the patients were comparedbefore and after initiation of the application to evaluate the degree ofmelasma improving according to the following criteria.

Evaluation Criteria of the Degree of Melasma Improvement Cured Allsymptoms disappeared Improvement Improvement of two grades or better bythe criteria of Table 1 achieved Slight improvement Improvement wasobserved: less than two grades by the criteria of Table 1 No change oraggravation No improvementTest Results

The obtained results are shown in Table 2. Table 2 shows the number ofpatients that met each of the above evaluation criteria of the melasmaimproving grade, the proportion of “slight improvement” or better (theproportion (%) of patients that showed “slight improvement” or better),and the 95% confidence interval of the percentage of patients with“slight improvement” or better, 4, 8, 12, and 16 weeks after initiationof the application. TABLE 2 Degree of melasma Proportion of improvement(the number of the patients) slight 95% Slight No change or improvementconfidence Cured Improvement improvement aggravation or better (%)interval  4 weeks after 0 0 5 22 18.5  6.3-38.1 initiation of theexternal application  8 weeks after 0 5 10 12 55.6 35.3-74.5 initiationof the external application 12 weeks 0 10 10 7 74.1 53.7-88.9 afterinitiation of the external application 16 weeks 0 10 14 2 92.3 74.9-99.1after initiation of the external application

As is evident from Table 2, the remarkable effect of improving melasmawas exhibited by the use of emulsions comprising AMP2Na. Morespecifically, 12 weeks after initiation of the external application,74.1% of the patients, and 16 weeks after initiation of the application,92.3% of the patients showed improvement of melasma, and it was foundthat the effect of improving melasma was statistically significant.

The above test results showed that the purine nucleic acid-relatedsubstance, when applied to the melasma lesion, exhibited an excellentmelasma improving effect, and thus it was found that the substance isuseful for improving melasma.

Test Example 2 Test for Reducing Skin Dullness

The following tests were conducted to evaluate the skin dullnessreduction effect of a purine nucleic acid-related substance.

Test Method

A suitable amount (an amount that can be uniformly applied to the entireface: about five drops) of the emulsion prepared according to theformulation of Example 1 was applied over the entire face of 27 femaleswith skin dullness, twice per day, after washing of the face, and thiswas continued for 16 weeks. Before initiation of the application, and 4,8, 12, and 16 weeks after initiation of the application, the skin colortone of the subjects was measured using a color difference meter(OFC-300A, Nippon Denshoku Industries Co., Ltd.). The measurement valuewas obtained by measuring a L* value indicating lightness of the skin,an a* value indicating redness of the skin, and a b* value indicatingyellowness of the skin of the evaluation target region of each patient11 times, and calculating the mean of 7 measurement values of 11 values,excluding the 2 maximum and 2 minimum values.

Test Results

The obtained results are shown in FIG. 1. FIG. 1 shows the mean averageof the variation, ΔL* of the L* value indicating skin lightness, themean average of the variation, Δa* of the value a* indicating redness,and the variation, ΔE*ab indicating color difference of the skin,(E*ab), 4, 8, 12, and 16 weeks after initiation of the application ascompared to the L* value, the a* value and the b* value of the subjectsbefore application of the composition. The ΔAE*ab value was calculatedby formula 1.ΔE*ab=[(ΔL*)²+(Δa*)²+(Δb*)²]^(1/2)  Formula 1

By the application of the emulsions comprising AMP2Na to the skin, theL* value of the skin (skin lightness) was significantly increased 4weeks after initiation of the application, while the b* value indicatingyellowness was significantly reduced 4 weeks after initiation of theapplication. The a* value indicating redness started to increase about 8weeks after initiation of the application, and the increase wassignificant 12 weeks after the initiation. The trend in the change ofthe a* value indicating redness showed that the change in the skinredness was not causedby the transient improvement in blood flow. It isknown that the ΔE*ab value as an index for showing a change in colordifference represents a total change in the skin with respect tolightness, redness, and yellowness, and in general the change in theskin can be subjectively and objectively observed when the Δ valuegenerally reaches 2 or higher. Since the ΔE*ab value 4 weeks afterinitiation of the application was already above 2, it was found that theskin color tone had already notably changed.

The above test results showed that the purine nucleic acid-relatedsubstance exhibits an excellent skin dullness reduction effect whenapplied to the dullness region of the skin, and thus it was found thatthe substance is useful for reducing the skin dullness.

Test Example 3 An Emulsion Stability Test for the Composition forImproving Melasma or Reducing Skin Dullness in an O/W Emulsified State

The following tests were conducted to evaluate the emulsion stability ofa composition for improving melasma or reducing skin dullness in an O/Wemulsified state.

Test Method

For evaluation of the emulsion stability test for a composition forimproving melasma or reducing skin dullness in an O/W emulsified state,a composition for improving melasma or reducing skin dullness wasprepared according to the formulation shown in Table 3. First, apolyglyceryl fatty acid ester, an alkanoyl lactate, an oil, and apolyhydric alcohol were blended, dissolved while being heated, andcooled, to prepare a uniform nonaqueous emulsion. Mixed therewith was anaqueous composition (aqueous solution) that was separately prepared bydissolving in distilled water (pure water) an electrolyte, an acrylicacid-alkyl methacrylate copolymer, a polyhydric alcohol, a loweralcohol, a pH adjuster, and an antiseptic. The mixture was stirred by ahomomixer to give a composition for improving melasma or reducing skindullness in an O/W emulsified state (Examples 2 to 5). For comparison, acomposition for improving melasma comprising no alkanoyl lactate(Comparative Example 1), and a composition for reducing skin dullnesscomprising no acrylic acid-alkyl methacrylate copolymer (ComparativeExample 2) were prepared in the same manner as in Examples 2 to 5 (Table4 shows the ingredients for these emulsion compositions).

The ten compositions for improving melasma or reducing skin dullness(Examples 2 to 5 and Comparative Examples 1 and 2) thus prepared wereeach placed in two transparent glass bottles. One bottle was left tostand at a temperature of 60° C. for 2 weeks, and the other bottle wassubjected to a 14-cycle test at temperatures ranging from −5° C. to 40°C. (1 cycle: 24 hours). The appearance (separation, oil floating,presence/absence of gel formation) of each emulsion composition afterthe test was visually observed and evaluated according to the followingcriteria.

<Evaluation Criteria>

-   A: Neither separation, oil floating, nor gel formation was observed.

B: Separation, oil floating, or gel formation was observed. TABLE 3 Ex.2 Ex. 3 Ex. 4 Ex. 5 1 Decaglycerol — 1.6 0.16 4.8 monoisostearate 2Decaglycerol 1.2 — — — diisostearate 3 Decaglycerol — — 0.02 0.5monostearate 4 Decaglycerol 0.6 0.2 — — monomyristate 5 Sodium stearoyl— — 0.02 — lactate 6 Sodium isostearoyl 0.2 0.2 — 0.5 lactate 7 Squalane5.0 8.0 — 15.0 8 α-Olefin oligomer — — 5.0 — 9 Purified glycerol 6.0 6.02.0 9.0 10 Dipropylene glycol — — 5.0 — 11 Disodium adenosine 1.5 1.53.0 6.0 monophosphate 12 Acrylic acid-alkyl 0.4 0.5 0.5 0.5 methacrylatecopolymer 13 Ethanol 5.0 5.0 3.0 5.0 14 pH Adjuster Suitable SuitableSuitable Suitable amount amount amount amount 15 Antiseptic SuitableSuitable Suitable Suitable amount amount amount amount 16 Pure waterRemainder Remainder Remainder Remainder Viscosity (cps) 20° C. 420017000 1400 1100 Long-term stability A A A A (60° C.: 2 weeks) Long-termstability A A A A (−5 to 40° C. cycles: 2 weeks)

TABLE 4 Comp Ex. 1 Comp Ex. 2 1 Decaglycerol monoisostearate 2.0 — 2Decaglycerol diisostearate — 1.2 3 Decaglycerol monomyristate — 0.6 4Sodium isostearoyl lactate — 0.2 5 Squalane 5.0 — 6 α-Olefin oligomer —5.0 7 Purified glycerol 6.0 8.0 8 Carboxyvinyl polymer — 0.6 9 Disodiumadenosine 3.0 3.0 monophosphate 10 Acrylic acid-alkyl 0.5 — methacrylatecopolymer 11 Ethanol 3.0 5.0 12 pH Adjuster Suitable amount Suitableamount 13 Antiseptic Suitable amount Suitable amount 14 Pure waterRemainder Remainder Viscosity (cps) 20° C. 2,000 1,200 Long-termstability A B (60° C.: 2 weeks) Long-term stability B A (−5 to 40° C.cycles: 2 weeks)Test Results

Tables 3 and 4 show the results of the emulsion stability test for thecompositions for improving melasma of Examples 2 to 5 and ComparativeExamples 1 and 2.

As can be seen from the tables 3 and 4, the compositions for improvingmelasma or reducing skin dullness in an O/W emulsified state of Examples2 to 5 inhibit water/oil phase separation, oil floating and gelformation and stably maintains their emulsified state under conditionsin which the emulsion compositions are likely to be affected bylong-term storage and temperature change, even when they contain arelatively large amount of AMP2Na. In contrast, as the comparativeexamples show, the emulsion composition in an O/W emulsified statecomprising no acrylic acid-alkyl methacrylate copolymer (ComparativeExample 2) lacked long-term emulsion stability, and the emulsioncomposition comprising no alkanoyl lactate (Comparative Example 1)gelated with temperature change, thus failing to maintain a stableemulsified state.

As is clear from the above, when formulated into an O/W emulsioncomposition as previously described, the composition for improvingmelasma or reducing the skin dullness can be provided in the form ofemulsions or creams in a stable manner.

INDUSTRIAL APPLICABILITY

The composition for improving melasma of the invention exhibits anexcellent melasma improving effect due to the action of the purinenucleic acid-related substance when applied to a melasma lesion.

The composition for reducing skin dullness of the invention exhibits anexcellent effect of reducing the skin dullness due to the action of thepurine nucleic acid-related substance when applied to a dullness regionof the skin.

The purine nucleic acid-related substance included as an activeingredient in the composition for improving melasma or for reducing skindullness is highly safe to the human body since such a substance isintrinsically present in the living body. Thus, the substance can beincluded in cosmetics in addition to externally-applied medical orquasi-medical drugs. Therefore, the present invention provides ameansfor improving melasma or skin dullness which can be carried out by thedaily use of a cosmetic comprising the substance, and thus is easy forpatients to use.

Further, the composition for improving melasma or reducing skin dullnessin an O/W emulsified state of the invention has a favorable emulsionstability in addition to an excellent effect for improving melasma orreducing the skin dullness, and thus is useful as an externally-appliedagent for the skin in the form of a cream or emulsion.

The method for improving melasma of the invention makes it possible toeffectively improve melasma.

The method for reducing skin dullness of the invention makes it possibleto effectively reduce the skin dullness.

1. A composition for improving melasma comprising a purine nucleicacid-related substance, and a pharmaceutically or cosmeticallyacceptable carrier.
 2. A composition for improving melasma according toclaim 1, wherein the purine nucleic acid-related substance is anadenosine monophosphate or a salt thereof.
 3. A composition forimproving melasma according to claim 1, comprising the purine nucleicacid-related substance in a proportion of at least 0.01 wt. % based onthe total amount of a composition.
 4. A composition for improvingmelasma according to claim 1, comprising the purine nucleic acid-relatedsubstance in a proportion of 1 to 10 wt. % based on the total amount ofa composition.
 5. A composition for improving melasma according to claim1, wherein the composition further comprises a polyglyceryl fatty acidester, an alkanoyl lactic acid or a salt thereof, an acrylic acid-alkylmethacrylate copolymer, water, and an oil, and is formulated into anO/W-type emulsification.
 6. A composition for improving melasmaaccording to claim 5, further comprising a polyhydric alcohol.
 7. Acomposition for improving melasma according to claim 5, wherein thepolyglyceryl fatty acid ester is an ester of a C₁₂₋₃₆ fatty acid and apolyglycerol having a polymerization degree of 6 or more, the alkanoyllactic acid comprises an alkanoyl group having 8 or more carbons, theacrylic acid-alkyl methacrylate copolymer comprises a C₅₋₄₀ alkyl group,and the oil is a hydrocarbon liquid oil.
 8. A composition for improvingmelasma according to claim 6, wherein the polyglyceryl fatty acid esteris included in a proportion of 0.05 to 6 wt. %, the alkanoyl lactic acidor a salt thereof is included in a proportion of 0.01 to 1 wt. %, theacrylic acid-alkyl methacrylate copolymer is included in a proportion of0.01 to 0.8 wt. %, the oil is included in a proportion of 0.3 to 20 wt.%, the polyhydric alcohol is included in a proportion of 0.05 to 15 wt.%, and water is included in a proportion of 50 to 90 wt. %, based on thetotal amount of the composition.
 9. A composition for improving melasmaaccording to claim 5, wherein the polyglyceryl fatty acid ester and thealkanoyl lactic acid or a salt thereof are included in a weight ratio of95:5 to 60:40.
 10. A composition for improving melasma according toclaim 5, further comprising a lower alcohol.
 11. A composition forreducing skin dullness comprising a purine nucleic acid-relatedsubstance, and a pharmaceutically or cosmetically acceptable carrier.12. A composition for reducing skin dullness according to claim 11,wherein the purine nucleic acid-related substance is an adenosinemonophosphate or a salt thereof.
 13. A composition for reducing skindullness according to claim 11, comprising the purine nucleicacid-related substance in a proportion of at least 0.01 wt. % based onthe total amount of the composition.
 14. A composition for reducing skindullness according to claim 11, comprising the purine nucleicacid-related substance in a proportion of 1 to 10 wt. % based on thetotal amount of the composition.
 15. A composition for reducing skindullness according to claim 11, wherein the composition furthercomprises polyglyceryl fatty acid ester, an alkanoyl lactic acid or asalt thereof, an acrylic acid-alkyl methacrylate copolymer, water, andan oil, and is formulated into an O/W-type emulsification.
 16. Acomposition for reducing skin dullness according to claim 15, furthercomprising a polyhydric alcohol.
 17. A composition for reducing skindullness according to claim 15, wherein the polyglyceryl fatty acidester is an ester of a C₁₂₋₃₆ fatty acid and a polyglycerol having apolymerization degree of 6 or more, the alkanoyl lactic acid comprisesan alkanoyl group having 8 or more carbons, the acrylic acid-alkylmethacrylate copolymer comprises a C₅₋₄₀ alkyl group, and the oil is ahydrocarbon liquid oil.
 18. A composition for reducing skin dullnessaccording to claim 16, wherein the polyglyceryl fatty acid ester isincluded in a proportion of 0.05 to 6 wt. %, the alkanoyl lactic acid ora salt thereof is included in a proportion of 0.01 to 1 wt. %, theacrylic acid-alkyl methacrylate copolymer is included in a proportion of0.01 to 0.8 wt. %, the oil is included in a proportion of 0.3 to 20 wt.%, the polyhydric alcohol is included in a proportion of 0.05 to 15 wt.%, and water is included in a proportion of 50 to 90 wt. %, based on thetotal amount of the composition.
 19. A composition for reducing skindullness according to claim 15, wherein the polyglyceryl fatty acidester and the alkanoyl lactic acid or a salt thereof are included in aweight ratio of 95:5 to 60:40.
 20. A composition for reducing skindullness according to claim 15, further comprising a lower alcohol. 21.A method for improving melasma, comprising applying a purine nucleicacid-related substance to a melasma lesion.
 22. A method for reducingskin dullness, comprising applying a purine nucleic acid-relatedsubstance to a dullness region of the skin.
 23. Use of a purine nucleicacid-related substance for preparing a composition for improvingmelasma.
 24. Use of a purine nucleic acid-related substance forpreparing a composition for reducing skin dullness.
 25. Use of a purinenucleic acid-related substance for improving melasma.
 26. Use of apurine nucleic acid-related substance for reducing skin dullness.